The purpose of this study is to evaluate effectiveness of directly observed, once-a-day, highly active antiretroviral therapy (HAART) in the sustained suppression of viral replication in HIV-infected substance abusers. Our specific aims include: l) To determine whether directly observed once-a- day HAART, administered over a twelve-month period, is more effective than self-administered once-a-day HAART in the suppression of plasma HIV RNA in substance abusers. 2) To evaluate and compare patterns of adherence in the DOT arm and the control arm during all phases of the study utilizing audio computer assisted self-interview (ACASI). 3) To compare the development of antiretroviral resistance between the DOT and standard of care arms. 4) To determine the effect of a period of DOT on subsequent plasma HIV RNA and patterns of adherence. We plan to enroll 120 HW-infected individuals with no more than 30 days of prior antiretroviral therapy and with a history of having used heroin or cocaine within the 90 days prior to enrollment. All patients will be treated with a once-a-day HAART regimen. Patients will be randomized to either a directly observed therapy (DOT) intervention arm or to a standard-of- care control arm in which medications are self-administered. All patients will receive comprehensive medical care at the Immunology Center, a multidisciplinary clinic devoted exclusively to the care of patients with HIV infection. The total study duration will be five years. In the initial intensive phase of the intervention (duration:12 months), patients in the DOT arm will be visited every day by an outreach worker who will deliver the daily dose of antiretroviral medication and observe the patient taking the dose. This phase will be followed by a tapering phase (duration: 6 months), during which the frequency of visits will be gradually decreased to once a week. Throughout the study period, adherence will be assessed by patient self-report in an ACASI questionnaire. HIV RNA quantification, drug resistance testing by genotype, and CD4+ cell count determinations will be used to assess the effect of DOT on virologic suppression and development of resistance. The ACASI questionnaire will be administered and sera collected for laboratory assays at baseline, 1,3,6,9,12,15,18,21, and 24 months.